PEG-Detachable Polymeric Micelles Self-Assembled from Amphiphilic Copolymers for Tumor-Acidity-Triggered Drug Delivery and Controlled Release

The development of an intelligent biomaterial system that can efficiently accumulate at the tumor site and release a drug in a controlled way is very important for cancer chemotherapy. PEG is widely selected as a hydrophilic shell to acquire prolonged circulation time and enhanced accumulation at the tumor site, but it also restrains the cellular transport and uptake and leads to insufficient therapeutic efficacy. In this work, a PEG-detachable pH-responsive polymer that forms micelles from copolymer cholesterol grafted poly(ethylene glycol) methyl ether-D-labile-poly(beta-amino ester)-D-labile-poly(ethylene glycol) methyl ether (MPEG-D-labile-PAE-g-Chol) is developed to overcome the aforementioned challenges based on pH value changes among normal physiological, extracellular (pH(e)), and intracellular (pH(i)) environments. PEGylated doxorubicin (DOX)-loaded polymeric micelles (DOX-PMs) can accumulate at the tumor site via an enhanced permeability and retention effect, and the PEG shell is detachable induced by cleavage of the pH(e)-labile linker between the PEG segment and the main chain. Meanwhile, the pH(i)-sensitive poly(beta-amino ester) segment is protonated and has a high positive charge. The detachment of PEG and protonation of PAE facilitate cellular uptake of DOX-PMs by negatively charged tumor cells, along with the escape from endo-/lysosome due to the "proton-sponge" effect. The DOX molecules are controlled release from the carriers at specific pH values. The results demonstrate that DOX-PMs have the capability of showing high therapeutic efficacy and negligible cytotoxicity compared with free DOX in vitro and in vivo. Overall, we anticipate that this PEG-detachable and tumor-acidity-responsive polymeric micelle can mediate effective and biocompatible drug delivery "on demand" with clinical application potential.